Neurons are some of the most highly polarized cells in the body and the polarization of axons and dendrites underlies the proper flow of information in the brain. Currently, the molecular mechanisms underlying neuronal polarization during brain development in vivo are unclear. Recent work from the Polleux lab and several other labs has started to define a signaling cascade required for cortical neuron polarization in vivo. At the core of this cascade is the phosphorylation of a serine/threonine kinase LKB1 on its Serine 431. Currently, the upstream mechanisms responsible for this phosphorylation event in vivo are unknown. I have obtained preliminary results suggesting that the serine/threonine kinase, TGF-P activated kinase 1 (TAK 1) phosphorylates S431 on LKB1 and my project is aimed at determining the biological relevance of TAK1 in the polarization of immature cortical neurons. Preliminary studies suggest that TAK1 is capable of phosphorylating LKB1 on the residue required for polarization and axon initiation, making it a potential upstream kinase required for triggering LKB1 polarizing function. The research objectives outlined in this proposal will be among the first to identify the major upstream kinase in the polarization signaling cascade as well as identify the required signaling partners and the major signaling molecule for the initiation of this cascade. First, I will determine the role of TAK1 in neuronal polarization using gain- and loss-of-function in vitro while utilizing a cortex-specific conditional TAK1 knockout mouse to determine its role in vivo. I will also examine the function of strong candidate proteins such as TAB1 and TAB2, known is non-neuronal cells to localize and activate TAK1. Finally, I will test if TGF-p is the major signaling molecule is responsible for the initiation of the polarization cascade. While TGF-p has been shown to activate TAK1 in other pathways, I will test if it is capable of activating TAK1 in cultured cortical neurons. This work will elucidate the role of TAK1 in cortical development and identify the signaling cascade upstream of LKB1 required for proper neuronal polarization in vivo. Understanding the signaling cascade responsible for proper neuronal polarization in vivo is one of the most essential step towards the establishment of a functional cortical connectivity. This project will lead to important new insights into the molecular mechanisms underlying the proper development of cortical connectivity which is disrupted in a wide range of developmental neuropathologies such Autism Spectrum Disorders, epilepsia and schizophrenia.